|Year : 2017 | Volume
| Issue : 5 | Page : 37-44
Role of epidermal growth factor receptor-tyrosine kinase inhibitors in the management of central nervous system metastases in epidermal growth factor receptor mutation-positive nonsmall cell lung cancer patients
U Batra1, N Lokeshwar2, S Gupta3, P Shirsath4
1 Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
2 Asian Cancer Institute, Somaiya Ayurvihar, Mumbai, Maharashtra, India
3 Max Super Speciality Hospital, Mohali, Punjab, India
4 Medical Advisor Oncology, Medical Affairs, AstraZeneca, India
|Date of Web Publication||29-Dec-2017|
Dr. U Batra
Rajiv Gandhi Cancer Institute and Research Centre, New Delhi
Source of Support: None, Conflict of Interest: None
Metastases to central nervous system (CNS) are very common in nonsmall cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-positive mutation. Brain is the most affected part of CNS where blood–brain barrier (BBB) presents a challenge to currently available chemotherapeutic agents as well as first- (erlotinib and gefitinib) and second (afatinib)-generation EGFR tyrosine kinase inhibitors (TKIs) due to their poor penetrability. A rapid development of EGFR T790M secondary mutation is another cause of treatment failure, and patients tend to progress despite initial response to first- and second-generation EGFR TKIs. Moreover, conventional treatments with heavy dose of radiation have a number of side effects compared to benefits attained. Recently, third-generation EGFR TKIs have been developed with proven efficacy in various clinical setups against EGFR mutation-positive cases of brain metastases in NSCLC. One such agent, osimertinib, is available in India. It has not only better penetration ability to BBB compared to other EGFR TKIs but also has significantly increased potency for most prevalent EGFR T790M mutations. Furthermore, it is active in patients who progress upon first- and second-generation EGFR TKIs. The purpose of this review article is to present an updated clinical preview of EGFR TKIs over conventional treatment, mainly radiation therapy to consider them as “use first” agents against EGFR T790M mutation in the treatment of patients with advanced NSCLC.
Keywords: Brain metastases, Epidermal growth factor receptor, Osimertinib, Non-small cell lung cancer, T790M, Tyrosine kinase inhibitors
|How to cite this article:|
Batra U, Lokeshwar N, Gupta S, Shirsath P. Role of epidermal growth factor receptor-tyrosine kinase inhibitors in the management of central nervous system metastases in epidermal growth factor receptor mutation-positive nonsmall cell lung cancer patients. Indian J Cancer 2017;54, Suppl S1:37-44
|How to cite this URL:|
Batra U, Lokeshwar N, Gupta S, Shirsath P. Role of epidermal growth factor receptor-tyrosine kinase inhibitors in the management of central nervous system metastases in epidermal growth factor receptor mutation-positive nonsmall cell lung cancer patients. Indian J Cancer [serial online] 2017 [cited 2021 Sep 28];54, Suppl S1:37-44. Available from: https://www.indianjcancer.com/text.asp?2017/54/5/37/221924
| » Introduction|| |
Lung cancer accounts for 19% of cancer-related deaths worldwide, whereas, in India, this number constitutes 9.3%. According to GLOBOCAN 2012 report, lung cancer was ranked fourth overall among the various types of cancer after breast, cervical, and oral cavity in India. Lung cancers can be histologically subtyped as nonsmall cell lung cancer (NSCLC) and small cell lung cancer, of which NSCLC accounts for approximately 85%. Distant metastases at the time of presentation of NSCLC are a frequent clinical problem. Approximately 30%–40% of NSCLC patients present with metastatic disease at the time of diagnosis., The most common metastatic site is bone, followed by the lungs, brain, liver, and adrenal glands.
Approximately 7.4% of patients have brain metastases (BMs) at baseline, and about 20%–40% of patients develop it as disease progression., The majority of BMs (80%) occur in the cerebral hemispheres, 15% in the cerebellum, and 5% in the brain stem. The reported median survival of these patients is 3.4 months with poor life expectancy. In addition, many suffer a substantial loss of autonomy because of neurocognitive and functional deficits, as well as morbidity associated with medications such as antiepileptic drugs and steroids. Treatment options available for BM include surgery, whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), systemic chemotherapy, molecular-targeted drugs, immunotherapy, and combination therapy, of which WBRT is regarded as the standard therapy but not without a downside of abundant neurotoxic side effects. With technological and molecular diagnostic advancements, SRS and targeted therapy are coming up in a big way for the treatment of BM with less toxic complications.
It is now revealed that many of the NSCLC clones are driven by a certain set of mutations which lead to altered signal transduction pathways. One such pathway is the epidermal growth factor receptor (EGFR) signaling pathway, wherein activating (sensitizing) mutations in tyrosine kinase (TK) domain result in reduced responses to chemotherapy. Activating mutations of the EGFR kinase domain are present in 10%–15% of patients with lung adenocarcinoma in North America and up to 60% of patients in Asia. Patients with EGFR-mutant NSCLC may have a higher likelihood of being diagnosed with BMs because of prolonged survival from targeted systemic agents and the increased quality of central nervous system (CNS) imaging.
Patients with EGFR-mutant NSCLC may have a higher probability of having BM. Therefore, prognosis of NSCLC patients with BM may also be associated with the status of EGFR mutations. Novel targeted EGFR tyrosine kinase inhibitors (TKIs) namely erlotinib, gefitinib ( first generation), and afatinib (second generation) are available and now considered as first-line treatment in EGFR mutation-positive NSCLC patients. These agents have demonstrated superior clinical benefits in various randomized clinical trials compared with chemotherapy.
However, most of the patients develop acquired resistance to first- and second-generation EGFR TKIs during the course of the treatment, and one of the common acquired mutations of clinical relevance is T790M mutation (50%–60% of all resistance cases) in EGFR TK domain. Moreover, treatment in case of BM remains a challenge due to their poor blood–brain barrier (BBB) penetration ability. Recently, the third-generation EGFR inhibitors, namely, osimertinib, rociletinib, HM61713, and others have emerged as potential therapeutics with better BBB penetration capabilities. More importantly, third-generation TKIs have a significantly increased potency for most prevalent EGFR T790M mutations as compared to first- and second-generation EGFR TKIs.
The purpose of this article is to highlight the better BBB-penetrating ability of third-generation EGFR TKI osimertinib, and hence its importance in the treatment of EGFR T790M mutation-positive patients with BM, who progress upon first- and second-generation EGFR TKIs. The entire information has been aligned to create an awareness in the medical fraternity about the benefits of EGFR TKIs over conventional treatment, mainly radiation therapy, to consider this class of drugs as “use first” agents while starting the treatment.
| » Brain Metastases and Mutational Status of Nonsmall Cell Lung Cancer|| |
Over the past decade, patients of NSCLC have been further defined at the molecular level on the bases of recurrent “driver” mutations that occur in multiple oncogenes including AKT1, anaplastic lymphoma kinase (ALK), BRAF, EGFR, FGFR1, HER2, KRAS, MEK1, MET, NRAS, PIK3CA, RET, and ROS1. However, EGFR mutations have been widely explored and seem to have significant implications in deciding targeted therapy in metastatic NSCLC [Table 1]. In a retrospective analysis, relationship between EGFR mutation status and BM at the initial presentation was analyzed. A strong association between EGFR mutation status and BM was found (adjusted odds ratio = 3.83, P = 0.001); nevertheless, no association was observed between EGFR mutation status and extracranial metastases (adjusted odds ratio = 1.73, P = 0.079).
|Table 1: Epidermal growth factor receptor mutation status in patients with nonsmall cell lung cancer and brain metastases|
Click here to view
In addition, multiple investigators have now reported several lines of evidence involving the importance of liver kinase B1 (LKB1, aka, serine-threonine kinase 11) as a tumor suppressor gene in lung cancer development and progression in both human and model organisms. Moreover, coordination between losses of LKB1 and the oncogene, KRAS, also predicted BM in NSCLC patients.
Moreover, adenocarcinomas with FGFR1 gene amplification and ALK1 rearrangement correlated significantly with BM. FGFR1 amplifications in BM of adenocarcinomas were fivefold more frequent than in the primary tumors. Moreover, CXCR4 protein seems to play a role in BM. It had been observed that CXCR4 protein was overtly overexpressed in patients with brain-specific metastases compared to NSCLC patients with metastases in other organ and without metastases. Another factor ADAM9 levels were found to be relatively higher in BM than the levels observed in primary lung tumors. ADAM9 regulates lung cancer metastases to the brain by facilitating the tPA-mediated cleavage of CDCP1.
| » Prognosis of Nonsmall Cell Lung Cancer Patients With Brain Metastases|| |
Age, number of brain lesions, performance status, and the presence of extracranial metastases are the variables that better define prognosis. The Radiation Therapy Oncology Group (RTOG) performed a recursive partitioning analysis (RPA) from a historical database, where 1200 patients were treated with WBRT from three RTOG BM trials and published a prognostic scoring system. Three scoring classes were identified based on patients' Karnofsky performance score, age, status of primary tumor, and extent of extracranial disease [Table 2]. Median survival ranged from 2.3 months for patients in Class III to 7.1 months for those in Class I. The RPA system can be applied to any patient with a BM, but a newer prognostic index, the diagnosis-specific graded prognostic assessment (GPA) score, provides a higher level of refinement where the median survival ranges from 2.79 to 25.3 months. The GPA accounts for primary tumor type and unique features applicable to each primary tumor, making the system relevant to daily clinical practice.
Molecular biomarkers such as EGFR (del-19 and L858R) have positive, and others have negative (e.g., ERCC1, BRCA1, TP53, and KRAS) prognostic value. It has been reported that among patients with a druggable oncogene driver (EGFR and ALK), between 44% and 60%, develop BM in the course of their disease.
| » Management of Brain Metastases in Nonsmall Cell Lung Cancer|| |
A summary of recommendations for the management of BM in NSCLC patients has been presented in [Table 3]. The approach to treat NSCLC patient with BM is based on each patient's clinical condition. The classical treatment approach for BM is WBRT. However, NSCLC has been regarded as a relatively radio-resistant malignancy, and the usual dose of WBRT may not be sufficient to eradicate the lesions. Moreover, there remains a possibility of neurocognitive decline due to radiation. In addition, associated side effects further worsen the patients' health and have a negative impact on quality of life (QoL).
|Table 3: Recommendations for the management of brain metastases in nonsmall cell lung cancer patients,|
Click here to view
WBRT-related toxicities have been enlisted in [Table 4].
Recently, a survival benefit has been reported for patients with a single BM treated with SRS; however, due to the poor performance status, many patients with BM are not eligible for surgery or radiosurgery. Furthermore, the role of systemic chemotherapy for the treatment of BM is controversial due to the impenetrable nature of the BBB, with reported response rates to chemotherapy ranging from 15% to 30% (overall survival: 6–8 months). It is well-established fact now that treatment of EGFR mutation-positive patients with BM require different approaches. Such patients should receive EGFR TKI first and then delay brain irradiation until either CNS imaging or symptom progression, to delay WBRT-related neurological sequels.
Role of first- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors in the treatment of nonsmall cell lung cancer patients with brain metastases
Most recent clinical trials have reported the superior efficacy of first- and second-generation EGFR TKIs in EGFR-positive patient population [Table 5]. Overall, the data reported suggest that EGFR mutation may play a key role in the activity of EGFR TKIs, even in the presence of BM.
|Table 5: Current clinical trials on first- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors for epidermal growth factor receptor mutation positive nonsmall cell lung cancer patients|
Click here to view
Blood brain barrier penetration ability of first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors
First- and second-generation EGFR TKIs have proven efficacy in the treatment of intracranial BM. However, they may not achieve desired target concentration due to poor penetration of the BBB. Evidences suggest that both erlotinib and gefitinib have limited concentrations in cerebrospinal fluid (CSF) despite their small molecular size., In fact, at standard dose of erlotinib and gefitinib, CSF levels are lower than plasma levels. Preclinical studies demonstrated that EGFR TKIs are a substrate of BCRP1 and P-gp, drug efflux transporters. Therefore, these transporters may be responsible for reduced brain penetration of erlotinib and gefitinib.
Based on the pharmacokinetic data and the reduced efficacy of these agents in BM, TKIs seem to have limited access to CNS metastases compared with extracranial metastases. The limited CNS exposure of TKIs can explain the high incidence of BM in EGFR-mutated NSCLC despite the good control of extracranial disease during EGFR TKIs therapy. It is also evident that BM can damage the integrity of BBB and therefore may favor TKIs penetration. Hence, erlotinib and gefitinib at the standard dose may penetrate BBB in the presence of BM and improve their CNS concentration with a consequent improvement in central activity.
Furthermore, greater penetration of erlotinib and gefitinib has been observed at higher doses, which allows EGFR TKIs to exert greater activity in CNS. However, this dose escalation is inevitably linked with more frequent and significant side effects such as high-grade fatigue, nausea, and liver damage. Although afatinib shows incomplete penetration to BBB, it has potential to treat CNS metastases effectively due to lower median inhibitory concentration compared to erlotinib and gefitinib as shown in in vitro studies. Hence, afatinib appears to penetrate into the CNS with concentrations high enough to have clinical effect on CNS metastases. [Table 6] summarizes the details of penetration characteristics of first- and second-generation EGFR TKIs.
|Table 6: Central nervous system penetration of first- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors in patients with nonsmall cell lung cancer and brain metastases|
Click here to view
| » T790m Mutation and Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors|| |
Although NSCLC patients harboring EGFR-sensitizing mutations derive significant clinical advantage from EGFR TKIs therapy, after about 9–13 months from the beginning of treatment, disease progression occurs. This is because acquired resistance develops due to further mutations in TK domain. The most important mutation is T790M in exon 20, which is associated with ~62% of the patients with acquired resistance to first-generation EGFR TKIs. In this point, mutation T790M, methionine substitutes for threonine at amino acid position 790 of EGFR gene. The substitution of methionine with threonine at position 790 in the exon 20 blocks the binding of first-generation EGFR TKIs to the ATP pocket and increases their affinity to ATP rather than to EGFR TKIs. Re-biopsy results of various samples demonstrated that EGFR T790M mutation was present in approximately 50%–60% of resistant cases. Therefore, EGFR T790M mutation has emerged as a major culprit in developing acquired resistance against first- and second-generation EGFR TKIs.,,
Third-generation EGFR TKIs (osimertinib, rociletinib, HM61713, and others) have been evolved as T790M mutant-specific inhibitors. Initial data support their efficacy and safety in NSCLC patients with BM. AZD9291 (osimertinib), a novel third-generation TKI, specifically and irreversibly binds the cysteine-797 residue in the ATP-binding site of EGFR. It has recently obtained the accelerated Food and Drugs Administration approval in -mutated NSCLC with documented T790M resistance mutation.
CO1886 (rociletinib) is another irreversible third-generation mutant-selective EGFR TKI, specifically directed against common sensitizing EGFR mutations and T790M. Rociletinib had initially garnered great attention but has now been abandoned because of the initial reported ORR of 59% has been reduced to 45%. Moreover, side effect profile of rociletinib has also raised concerns about the optimal pathway forward. Results of activity in BM of other third-generation TKIs such as ASP8273, EGF816, and HM61713 are still awaited.
Osimertinib - The third-generation agent
Recently, with the introduction of third-generation EGFR TKI, osimertinib in the US (November 2015) and European market (February 2016), the treatment has become possible in T790M mutant-positive advanced NSCLC patients who acquired resistance in the due course of first- and second-generation EGFR TKIs treatment. Osimertinib (TAGRISSO™, AZD9291; AstraZeneca, London, UK) is a mono-anilino-pyrimidine, orally available, irreversible, third-generation EGFR TKI, which inhibits EGFR, through the C797 amino acid covalent bond, both sensitizing mutations (exon 19 deletion, L858R) and double mutants harboring T790M at a ninefold lower concentration compared with wild-type EGFR.In vitro assays showed that osimertinib also possesses a certain grade of activity at clinically relevant concentration against ERBB2, ERBB3, ERBB4, BLK, and ACK1. Consistently, preclinical models involving NSCLC cell lines and tumor xenografts showed that osimertinib exerts an impressive activity against those tumors harboring L858R, exon 19 deletions alone, or in coexistence with T790M mutations.
Efficacy of osimertinib in various clinical studies
A joint analysis of AURA and AURA 2 studies reported that 39% of total enrolled patients (162/411) had BM. The systemic ORR of overall population was 61%, and it became 56% and 64% in patients with or without BM, respectively. In addition, cases of shrinkage of brain lesions were also reported. Preliminary antitumor activity of osimertinib in the brain has been reported in the Phase I BLOOM trial. Moreover, the ongoing Phase III first-line FLAURA trial (NCT02296125), which is comparing osimertinib with erlotinib or gefitinib as first-line treatment in patients with common EGFR mutations will define whether a third-generation EGFR TKI could become standard first-line treatment in these patients. Currently, the Real-World Treatment Study of osimertinib for Advanced/Metastatic EGFR T790M Mutation NSCLC (ASTRIS) is going on to assess the efficacy and safety of single-agent osimertinib in a real-world setting in EGFR T790M mutation-positive NSCLC, who have received prior EGFR TKIs therapy. Results of most recent clinical trials support osimertinib to be recommended as first-line therapy in NSCLC patients with T790M EGFR mutation and who progressed upon first- and second-generation EGFR TKIs. The results have been summarized below.
Bloom trial: Blood–brain barrier penetration ability of osimertinib in patients with leptomeningeal metastases
Leptomeningeal metastases (LMs) occur in almost 5% of NSCLC patients with median survival of 4–6 weeks. In the BLOOM study (NCT02228369), twenty patients with EGFR mutation advanced NSCLC who had progressed on prior EGFR TKI therapy and had LM confirmed by positive CSF cytology received, osimertinib 160 mg once daily (qd). Response was assessed (by investigator) in two cohorts: T790M unselected and T790M positive (by central test). It was demonstrated that osimertinib penetrates the BBB. Mean concentration of osimertinib in CSF was 7.51 nM (range: 2.19–21.1 nM) at steady state; CSF: free plasma ratio was 16%. Osimertinib demonstrated radiological improvement in 33% patients and stable disease in 43% patients. For CNS lesions, osimertinib was associated with clinically promising activity. Additional observations included confirmed CSF cytology clearance (i.e., no tumor cells) in two patients and confirmed improved neurologic function in five patients., Hence, encouraging activity and manageable tolerability in patients with LM from EGFR mutation-positive NSCLC was observed at 160 mg once daily dose of osimertinib, with a median treatment duration of 6 months.
AURA 3 clinical trial: Efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed
In this randomized Phase III trial, patients with T790M-positive advanced NSCLC, who had disease progression after first-line EGFR TKI therapy, received either oral osimertinib 80 mg once daily or intravenous pemetrexed in combination with carboplatin or cisplatin. The median progression-free survival (PFS) time and objective response rate were significantly greater with osimertinib than platinum therapy plus pemetrexed (P< 0.001). Among 144 patients with metastases to the CNS, the median duration of PFS was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio: 0.32; 95% confidence interval: 0.21–0.49). It was concluded that osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced NSCLC (including those with CNS metastases) in whom disease had progressed during first-line EGFR TKI therapy.
| » Conclusion|| |
It is common to develop EGFR-positive BM in advanced NSCLC patients. Although surgical resection and radiation therapy remain the cornerstone of treatment for symptomatic patients, a plentiful of neurological toxicities associated with the RT/WBRT further deteriorate neurocognitive disorders in patients with BM and affect their QoL. Despite the efficacy and superiority of first- and second-generation EGFR TKIs in the treatment of extracranial NSCLC over conventional therapy, treatment of CNS metastases remains a challenge primarily due to acquired T790M mutation and secondarily due to their poor BBB penetration ability. The next generation EGFR TKI osimertinib has improved BBB penetration and recent clinical trials supported its efficacy in BM patients, who progress upon first- and second-generation EGFR TKIs. Moreover, osimertinib has shown promising potency to inhibit the major resistance mutation, T790M in EGFR TK domain. The trends have been changing and now a general consensus is building up to try EGFR TKIs before proceeding to RT or surgery in EGFR-sensitive cases. Further trials are going on to determine the role of EGFR TKIs in combination with SRS and WBRT modalities.
The authors acknowledge AstraZeneca Pharma India Ltd., and Jeevan Scientific for Medical writing and editing support.
Financial support and sponsorship
Financial support to authors - Nil.
The supplement issue in which this article has been published has been sponsored by AstraZeneca Pharma India Ltd.
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Malik PS, Raina V. Lung cancer: Prevalent trends & emerging concepts. Indian J Med Res 2015;141:5-7.
] [Full text]
Noronha V, Pinninti R, Patil VM, Joshi A, Prabhash K. Lung cancer in the Indian subcontinent. South Asian J Cancer 2016;5:95-103.
] [Full text]
Little AG, Gay EG, Gaspar LE, Stewart AK. National survey of non-small cell lung cancer in the United States: Epidemiology, pathology and patterns of care. Lung Cancer 2007;57:253-60.
Matsuda A, Matsuda T, Shibata A, Katanoda K, Sobue T, Nishimoto H, et al.
Cancer incidence and incidence rates in Japan in 2008: A study of 25 population-based cancer registries for the monitoring of cancer incidence in Japan (MCIJ) project. Jpn J Clin Oncol 2014;44:388-96.
Tamura T, Kurishima K, Nakazawa K, Kagohashi K, Ishikawa H, Satoh H, et al.
Specific organ metastases and survival in metastatic non-small-cell lung cancer. Mol Clin Oncol 2015;3:217-21.
Owen S, Souhami L. The management of brain metastases in non-small cell lung cancer. Front Oncol 2014;4:248.
Sun CX, Li T, Zheng X, Cai JF, Meng XL, Yang HJ, et al
. Recursive partitioning analysis classification and graded prognostic assessment for non-small cell lung cancer patients with brain metastases: A retrospective cohort study. Chin J Cancer Res 2011;23:177-82.
D'Antonio C, Passaro A, Gori B, Del Signore E, Migliorino MR, Ricciardi S, et al.
Bone and brain metastasis in lung cancer: Recent advances in therapeutic strategies. Ther Adv Med Oncol 2014;6:101-14.
Li C, Fang R, Sun Y, Han X, Li F, Gao B, et al.
Spectrum of oncogenic driver mutations in lung adenocarcinomas from East Asian never smokers. PLoS One 2011;6:e28204.
Eichler AF, Chung E, Kodack DP, Loeffler JS, Fukumura D, Jain RK, et al.
The biology of brain metastases-translation to new therapies. Nat Rev Clin Oncol 2011;8:344-56.
Magnuson WJ, Lester-Coll NH, Wu AJ, Yang TJ, Lockney NA, Gerber NK, et al.
Management of brain metastases in tyrosine kinase inhibitor-naïve epidermal growth factor receptor-mutant non-small-cell lung cancer: A Retrospective multi-institutional analysis. J Clin Oncol 2017;35:1070-7.
Zheng Z, Jin X, Lin B, Su H, Chen H, Fei S, et al.
Efficacy of second-line tyrosine kinase inhibitors in the treatment of metastatic advanced non-small-cell lung cancer harboring exon 19 and 21 EGFR mutations. J Cancer 2017;8:597-605.
Porta R, Sánchez-Torres JM, Paz-Ares L, Massutí B, Reguart N, Mayo C, et al.
Brain metastases from lung cancer responding to erlotinib: The importance of EGFR mutation. Eur Respir J 2011;37:624-31.
Wang S, Cang S, Liu D. Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer. J Hematol Oncol 2016;9:34.
Tan CS, Cho BC, Soo RA. Treatment options for EGFR mutant NSCLC with CNS involvement-can patients BLOOM with the use of next generation EGFR TKIs? Lung Cancer 2017;108:29-37.
Hsu F, De Caluwe A, Anderson D, Nichol A, Toriumi T, Ho C, et al.
EGFR mutation status on brain metastases from non-small cell lung cancer. Lung Cancer 2016;96:101-7.
Shin DY, Na II, Kim CH, Park S, Baek H, Yang SH, et al.
EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol 2014;9:195-9.
Welsh JW, Komaki R, Amini A, Munsell MF, Unger W, Allen PK, et al.
Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J Clin Oncol 2013;31:895-902.
Lee HL, Chung TS, Ting LL, Tsai JT, Chen SW, Chiou JF, et al.
EGFR mutations are associated with favorable intracranial response and progression-free survival following brain irradiation in non-small cell lung cancer patients with brain metastases. Radiat Oncol 2012;7:181.
Gow CH, Chien CR, Chang YL, Chiu YH, Kuo SH, Shih JY, et al.
Radiotherapy in lung adenocarcinoma with brain metastases: Effects of activating epidermal growth factor receptor mutations on clinical response. Clin Cancer Res 2008;14:162-8.
Zhao N, Wilkerson MD, Shah U, Yin X, Wang A, Hayward MC, et al.
Alterations of LKB1 and KRAS and risk of brain metastasis: Comprehensive characterization by mutation analysis, copy number, and gene expression in non-small-cell lung carcinoma. Lung Cancer 2014;86:255-61.
Popper HH. Progression and metastasis of lung cancer. Cancer Metastasis Rev 2016;35:75-91.
Lin X, DeAngelis LM. Treatment of brain metastases. J Clin Oncol 2015;33:3475-84.
Novello S, Barlesi F, Califano R, Cufer T, Ekman S, Levra MG, et al.
Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016;27:v1-27.
Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman J, Chirieac LR, et al.
Non-small cell lung cancer, version 5.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2017;15:504-35.
Kim YH, Nagai H, Ozasa H, Sakamori Y, Mishima M. Therapeutic strategy for non-small-cell lung cancer patients with brain metastases (Review). Biomed Rep 2013;1:691-6.
Khuntia D. Contemporary review of the management of brain metastases with radiation. Adv Neurosci 2015;18:2015.
Sahgal A, Aoyama H, Kocher M, Neupane B, Collette S, Tago M, et al.
Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: Individual patient data meta-analysis. Int J Radiat Oncol Biol Phys 2015;91:710-7.
McTyre E, Scott J, Chinnaiyan P. Whole brain radiotherapy for brain metastasis. Surg Neurol Int 2013;4:S236-44.
] [Full text]
Dempke WC, Edvardsen K, Lu S, Reinmuth N, Reck M, Inoue A, et al.
Brain metastases in NSCLC – Are TKIs changing the treatment strategy? Anticancer Res 2015;35:5797-806.
Chen YM. Usage of EGFR-TKI and WBRT in NSCLC patients with brain metastases. Ann Palliat Med 2013;2:108-10.
Bai H, Xiong L, Han B. The effectiveness of EGFR-TKIs against brain metastases in EGFR mutation-positive non-small-cell lung cancer. Onco Targets Ther 2017;10:2335-40.
Dong H, Cui S, Pan F, Dong L, Niu Y, Zhao Y, et al.
Clinical experience with first-generation epidermal growth factor receptor Tyrosine kinase inhibitors in non-small cell lung cancer patients with brain metastasis. Zhongguo Fei Ai Za Zhi 2017;20:114-23.
Zheng MH, Sun HT, Xu JG, Yang G, Huo LM, Zhang P, et al.
Combining whole-brain radiotherapy with gefitinib/Erlotinib for brain metastases from non-small-cell lung cancer: A Meta-analysis. Biomed Res Int 2016;2016:5807346.
Park SJ, Kim HT, Lee DH, Kim KP, Kim SW, Suh C, et al.
Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer 2012;77:556-60.
Heon S, Yeap BY, Lindeman NI, Joshi VA, Butaney M, Britt GJ, et al.
The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations. Clin Cancer Res 2012;18:4406-14.
Ceresoli GL, Cappuzzo F, Gregorc V, Bartolini S, Crinò L, Villa E, et al.
Gefitinib in patients with brain metastases from non-small-cell lung cancer: A prospective trial. Ann Oncol 2004;15:1042-7.
Kim JE, Lee DH, Choi Y, Yoon DH, Kim SW, Suh C, et al.
Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis. Lung Cancer 2009;65:351-4.
Katayama T, Shimizu J, Suda K, Onozato R, Fukui T, Ito S, et al.
Efficacy of erlotinib for brain and leptomeningeal metastases in patients with lung adenocarcinoma who showed initial good response to gefitinib. J Thorac Oncol 2009;4:1415-9.
Yi HG, Kim HJ, Kim YJ, Han SW, Oh DY, Lee SH, et al.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for leptomeningeal metastasis from non-small cell lung cancer patients with sensitive EGFR mutation or other predictive factors of good response for EGFR TKI. Lung Cancer 2009;65:80-4.
Grommes C, Oxnard GR, Kris MG, Miller VA, Pao W, Holodny AI, et al.
“Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol 2011;13:1364-9.
Yang H, Yang X, Zhang Y, Liu X, Deng Q, Zhao M, et al.
Erlotinib in combination with pemetrexed/cisplatin for leptomeningeal metastases and cerebrospinal fluid drug concentrations in lung adenocarcinoma patients after gefitinib faliure. Target Oncol 2015;10:135-40.
Kawamura T, Hata A, Takeshita J, Fujita S, Hayashi M, Tomii K, et al.
High-dose erlotinib for refractory leptomeningeal metastases after failure of standard-dose EGFR-TKIs. Cancer Chemother Pharmacol 2015;75:1261-6.
Jackman DM, Cioffredi LA, Jacobs L, Sharmeen F, Morse LK, Lucca J, et al.
Aphase I trial of high dose gefitinib for patients with leptomeningeal metastases from non-small cell lung cancer. Oncotarget 2015;6:4527-36.
Gong L, Xiong M, Huang Z, Miao L, Fan Y. Icotinib might be effective for the treatment of leptomeningeal carcinomatosis in non-small cell lung cancer with sensitive EGFR mutations. Lung Cancer 2015;89:268-73.
Kwon J, Chie EK, Kim K, Kim HJ, Wu HG, Kim IH, et al.
Impact of multimodality approach for patients with leptomeningeal metastases from solid tumors. J Korean Med Sci 2014;29:1094-101.
Lee E, Keam B, Kim DW, Kim TM, Lee SH, Chung DH, et al.
Erlotinib versus gefitinib for control of leptomeningeal carcinomatosis in non-small-cell lung cancer. J Thorac Oncol 2013;8:1069-74.
Umemura S, Tsubouchi K, Yoshioka H, Hotta K, Takigawa N, Fujiwara K, et al.
Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama lung cancer study group. Lung Cancer 2012;77:134-9.
Wu C, Li YL, Wang ZM, Li Z, Zhang TX, Wei Z, et al.
Gefitinib as palliative therapy for lung adenocarcinoma metastatic to the brain. Lung Cancer 2007;57:359-64.
de Vries NA, Buckle T, Zhao J, Beijnen JH, Schellens JH, van Tellingen O, et al.
Restricted brain penetration of the tyrosine kinase inhibitor erlotinib due to the drug transporters P-gp and BCRP. Invest New Drugs 2012;30:443-9.
Zhao J, Chen M, Zhong W, Zhang L, Li L, Xiao Y, et al.
Cerebrospinal fluid concentrations of gefitinib in patients with lung adenocarcinoma. Clin Lung Cancer 2013;14:188-93.
Proto C, Imbimbo M, Gallucci R, Brissa A, Signorelli D, Vitali M, et al.
Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: The present and the future. Transl Lung Cancer Res 2016;5:563-78.
Baik CS, Chamberlain MC, Chow LQ. Targeted therapy for brain metastases in EGFR-mutated and ALK-rearranged non-small-cell lung cancer. J Thorac Oncol 2015;10:1268-78.
Hoffknecht P, Tufman A, Wehler T, Pelzer T, Wiewrodt R, Schütz M, et al.
Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol 2015;10:156-63.
Yufen X, Binbin S, Wenyu C, Jialiang L, Xinmei Y. The role of EGFR-TKI for leptomeningeal metastases from non-small cell lung cancer. Springerplus 2016;5:1244.
Deng Y, Feng W, Wu J, Chen Z, Tang Y, Zhang H, et al.
The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer. Mol Clin Oncol 2014;2:116-20.
Togashi Y, Masago K, Masuda S, Mizuno T, Fukudo M, Ikemi Y, et al.
Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol 2012;70:399-405.
Kawaguchi Y, Hanaoka J, Hayashi H, Mizusaki N, Iihara H, Itoh Y, et al.
Clinical efficacy of afatinib treatment for a patient with leptomeningeal carcinomatosis. Chemotherapy 2017;62:147-50.
Cortot AB, Jänne PA. Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas. Eur Respir Rev 2014;23:356-66.
Ettinger DS, Wood DE, Akerley W, Bazhenova LA, Borghaei H, Camidge DR, et al.
Non-small cell lung cancer, version 6.2015. J Natl Compr Canc Netw 2015;13:515-24.
Prabhakar CN. Epidermal growth factor receptor in non-small cell lung cancer. Transl Lung Cancer Res 2015;4:110-8.
Sequist LV, Soria JC, Camidge DR. Update to rociletinib data with the RECIST confirmed response rate. N
Engl J Med 2016;374:2296-7.
Tran PN, Klempner SJ. Profile of rociletinib and its potential in the treatment of non-small-cell lung cancer. Lung Cancer (Auckl) 2016;7:91-7.
Ricciuti B, Baglivo S, Paglialunga L, De Giglio A, Bellezza G, Chiari R, et al.
Osimertinib in patients with advanced epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer: Rationale, evidence and place in therapy. Ther Adv Med Oncol 2017;9:387-404.
Remon J, Menis J, Hasan B, Peric A, De Maio E, Novello S, et al.
The APPLE trial: Feasibility and activity of AZD9291 (Osimertinib) treatment on positive PLasma T790M in EGFR-mutant NSCLC patients. EORTC 1613. Clin Lung Cancer 2017;18:583-8.
Xu Q, Chen X, Qian D, Wang Y, Meng S, Liu H, et al.
Treatment and prognostic analysis of patients with leptomeningeal metastases from non-small cell lung cancer. Thorac Cancer 2015;6:407-12.
Yang JC, Cho BC, Kim DW, Kim SW, Lee JS, Su WC, et al.
Osimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): Updated results from the BLOOM study. J Clin Oncol 2017;35 Suppl 20:20.
Okuma Y, Hosomi Y. Osimertinib for advanced non-small cell lung cancer harboring EGFR mutation exon 20 T790M, acquired resistant mutation for first- or second-generation EGFR-TKI. J Thorac Dis 2017;9:470-3.
Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al.
Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N
Engl J Med 2017;376:629-40.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
|This article has been cited by|
||Integrating Osimertinib in Clinical Practice for Non-Small Cell Lung Cancer Treatment
| ||Senthil Rajappa,M. Vamshi Krishna,Prasad Narayanan |
| ||Advances in Therapy. 2019; 36(6): 1279 |
|[Pubmed] | [DOI]|